Opioid drugs have various effects on perception of pain, consciousness, motor control, mood, autonomic function, and can also induce physical dependence. The endogenous opioid system plays an important role in modulating endocrine, cardiovascular, respiratory, gastrointestinal functions, and immune functions. Opioids, either exogenous or endogenous, exert their actions by binding to specific membrane-associated receptors.
Examples of exogenous opioids presently known include, opium, heroin, morphine, codeine, fentanyl, and methadone, to name only a few. Moreover, a family of over 20 endogenous opioid peptides has been identified, wherein the members possess common structural features, including a positive charge juxtaposed with an aromatic ring that is required for interaction with an opioid receptor. It has been determined that most, if not all the endogenous opioid peptides are derived from the proteolytic processing of three precursor proteins, i.e., pro-opiomelanocortin, proenkephalin, and prodynorphin. In addition, a fourth class of endogenous opioids, the endorphins, has been identified (the gene encoding these proteins has not yet been cloned). In the processing of the endogenous opioid precursor proteins, initial cleavages are made by membrane-bound proteases that cut next to pairs of positively charged amino acid residues, and then trimming reactions produce the final endogenous opioids secreted from cells in vivo. Different cell types contain different processing enzymes so that, for example proopiomelanocortin can be processed into different endogenous peptides by different cells. For example, in the anterior lobe of the pituitary gland, only corticotropin (ACTH), β-lipotropin, and β-endorphin are produced. Both pro-enkephalin and pro-dynorphin are similarly processed by specific enzymes in specific cells to yield multiple opioid peptides.
Pharmacological studies have suggested there are numerous classes of opioid receptors which bind to exogenous and endogenous opioids. These classes differ in their affinity for various opioid ligands and in their cellular and organ distribution. Moreover, although the different classes are believed to serve different physiological functions, there is substantial overlap of function, as well as of distribution.
In particular, there are at least three known types of opioid receptors, mu (μ), delta (δ), and kappa (κ), to which morphine, the enkephalins, and the dynorphins can bind. These three opioid receptor types are the sites of action of opioid ligands producing analgesic effects. However, the type of pain inhibited and the secondary functions vary with each receptor type. The mu receptor is generally regarded as primarily associated with pain relief, and drug or other chemical dependence, i.e., addiction and alcoholism.
One such gene structurally related to the opioid receptor genes is the human kappa opioid (hKOR) receptor gene. The receptor is widely distributed in the CNS and periphery (including immune cells) and plays important and diverse roles in modulation of the endogenous opioid system, nociception, neurotransmitter release (including dopamine, GABA, and serotonin), learning, memory and cognition; cocaine, amphetamine and other stimulants self-administration; behavioral sensitization to cocaine, opiates, alcohol and tobacco; opiate, amphetamine and alcohol withdrawal, physical dependence and tolerance; neuroendocrine function, reproductive function, prolactin regulation, stress responsivity; physiology and pathology of mood and affect; immune function, and gastrointestinal function. See, for example, Simonin F, Valverde O, Smadja C, Slowe S, Kitchen I, Dierich A, Le Meur M, Roques B P, Maldonado R, Kieffer B L, 1998, Disruption of the kappa-opioid receptor gene in mice enchances sensitivity to chemical visceral pain, impaires pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal, EMBO J., 17: 886-897; Slowe S, Simonin F, Kieffer B, Kitchen I. 1999, Quantitative autoradiography of μ-, δ- and κ1-opioid receptors in k-opioid receptor knockout mice, Brain research, 818: 335-345; Heidbreder C A, Schenk S, Partridge B, Shippenberg T S. 1998, Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective kappa-opioid receptor agonist, Synapse, 30: 255-262; Schenk S, Partridge B, Shippenberg T S. 1999, U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking, Psychopharmacology (Berl), 144: 339-346; Kreek M J, Schluger J, Borg L, Gunduz M, Ho A. 1999, Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications for modulation of dopaminergic tone in the treatment of addictions. JPET, 288: 260-269; Portenoy R, Caraceni A, Cherny N I, Goldblum R, Ingham J, Inturrisi C E, Johnson J H, Lapin J, Tiseo P J, Kreek M J. 1999, Dynorphin A(1-13) analgesia in opioid-treated patients with chronic pain. Clin Drug Invest., 17: 33-42; Milan M J. 1990, κ-Opioid receptors and analgesia. TiPS, 11: 70-76; Mansson E, Bare L, Yang D., 1994, Isolation of human k opioid receptor cDNA from placenta, Bioch Biophys Res Communications, 202, 1431-1437; Simonin F, Gaveriaux-Ruff C, Befort K, Matthes H, lannes B, Micheletti G, Mattei M-G, Charron G, Bloch B, Kieffer B., 1995, k-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system, Proc Natl Acad Sci USA, 92, 7006-7010; Zhu J, Chen C, Xue J-C, Kunapuli S, DeRiel J K, Liu-Chen L-Y., 1995, Cloning of a human k opioid receptor from the brain, Life Sciences, 56, 201-207; Grandy D K., 1994, Mapping of the human kappa opioid receptor gene to chromosome 8q11.2-q12: no evidence for multiple kappa opioid receptor genes (partial sequence of exon II and downstream intron). GenBank entry, Accession # U16860; and Yasuda K, Espinosa R, Takeda J, Le Beau M M, Bell G I., 1995, Localization of kappa opioid receptor gene to human chromosome band 8q11.2 (sequence of exon II), GenBank entry, Accession # L26079. Three GenBank entries for hKOR are U17298, NM—000912, and L37362. These as well as all publications cited herein are incorporated herein by reference in their entireties.
It is toward the identification of both the wild-type human kappa opioid receptor gene as well as alleles other than the most common or wild-type allele of the human kappa opioid receptor gene, polymorphisms therein, and combinations of such polymorphisms that can be used as genetic markers to map the locus of the human kappa opioid receptor gene in the genome, and additionally to correlate such polymorphisms of the human kappa opioid receptor gene with susceptibility of a subject to any of the various physiological functions, conditions and diseases mentioned hereinabove in which the kappa opioid receptor gene plays a role, including but not limited to determine a subject's increased or decreased susceptibility to addictive diseases, susceptibility to pain and response to analgesics, physiological responses related to the endogenous opioid system, nociception, neurotransmitter release (including dopamine, GABA, and serotonin), learning, memory and cognition; cocaine, amphetamine and other stimulants self-administration; behavioral sensitization to cocaine, opiates, alcohol and tobacco; opiate, amphetamine and alcohol withdrawal, physical dependence and tolerance; neuroendocrine function, reproductive function, prolactin regulation, stress responsivity; physiology and pathology of mood and affect; immune function, and gastrointestinal function; among other uses, that the present invention is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.